Design, Synthesis, Drug-Likeness, anti-Inflammatory, Antimicrobial Activity, and Molecular Docking Studies of Pyrimidine Analogs

Abstract

Grounded on medicinal significances of pyrimidines, herein we are reporting initially the design and synthesis of 1-(2-benzylthiopyrimidin-4-yl)-benzimidazol-2-thioacetic acid/thioacetate 2(a, b), 1-(2-benzylthiopyrimidin-4-yl)-3,5 diaryl-2-pyrazoline (3) and 1-(2-benzylthiopyrimidin-4-yl)-3,5-dimethylpyrazole (4). In silico screening such as molecular docking studies of these compounds with inflammation-causing enzyme cyclooxagenase-2 (COX-2) suggests that only 2a has shown a strong affinity for the COX-2 (−9.0 kcal/mol) and forms three hydrogen bonds with active amino acid residues in comparison with standard anti-inflammatory drugs celecoxib (-8.8 kcal/mol) and indomethacin (-7.7 kcal/mol). However, in vitro, anti-inflammatory activity reveals that IC₅₀ of compound 2a was 3.5 μM compared to celecoxib with IC₅₀ of 0.65 μM. Also, 2a has displayed comparable activity of standard antibacterial drug gentamycin against E. coli with MIC 6.5 μM. Furthermore, the drug-likeness of potent compounds was studied using Swiss ADME and Mol inspiration software. All the compounds showed optimum drug-likeness without violating Lipinski’s rule of five. With our best observation and based on comparative SAR studies of these analogs with celecoxib and indomethacin, we conclude that compound 2a could develop as a therapeutically potent anti-inflammatory agent.

Keywords:

• Pyrimidines
• benzimidazoles
• pyrazoles
• and COX-2 inhibitors

Acknowledgement

The authors acknowledge Dr. S. M. Basavarajaiah. PG. Department of Chemistry, R.V. Road, Vijaya College, Bengaluru-560004, Karnataka, India, for suggestions on anti-inflammatory activity. The authors are also thankful to Dr. Malairasa Pandian, Department of Life Sciences, IADC-A, Bengaluru-560043, Karnataka, India, for the information on molecular docking studies. Thanks are due to Management, Indian Academy Degree College, Bengaluru for providing all the necessary facilities to carry out research work.

Authors’ contributions

Jeelan Basha N: Involved in conceptualization, methodology, software, data curation, writing—original draft preparation, writing—reviewing and editing, and supervision. Akshay KT: Took part in writing—reviewing and editing, methodology, and software.

Disclosure statement

The authors report no conflict of interest.

Data availability statement

Data will be produced on request.

Additional information

Funding

This work is supported by the IADC-A seed grant-2021/ No. 003.